OMICS Group

Contact us at: contact.omics@omicsonline.org

OMICS Group International through its Open Access Initiative is committed to make

genuine and reliable contributions to the scientific community. OMICS Group hosts

over 400 leading-edge peer reviewed Open Access Journals and organizes over 300

International Conferences annually all over the world. OMICS Publishing Group

journals have over 3 million readers and the fame and success of the same can be

attributed to the strong editorial board which contains over 30000 eminent

personalities that ensure a rapid, quality and quick review process. OMICS Group

signed an agreement with more than 1000 International Societies to make healthcare

information Open Access.

OMICS Group welcomes submissions that are original and

technically so as to serve both the developing world and

developed countries in the best possible way.

OMICS Journals are poised in excellence by publishing high

quality research. OMICS Group follows an Editorial

Manager® System peer review process and boasts of a strong

and active editorial board.

Editors and reviewers are experts in their field and provide

anonymous, unbiased and detailed reviews of all submissions.

The journal gives the options of multiple language

translations for all the articles and all archived articles are

available in HTML, XML, PDF and audio formats. Also, all

the published articles are archived in repositories and

indexing services like DOAJ, CAS, Google Scholar,

Scientific Commons, Index Copernicus, EBSCO, HINARI

and GALE.

For more details please visit our website: http://omicsonline.org/Submitmanuscript.php

OMICS Journals are welcoming Submissions

Birendra N. Mallick School of Life Sciences, Jawaharlal Nehru University, New Delhi, India

remsbnm@yahoo.com

GABA in locus coeruleus in REMS regulation

Presentation for

J. Sleep Dis. Therapy

SLEEP AND WAKING ARE INSTINCT

BEHAVIORS AND THEY REPRESENT

STATES OF CONSCIOUSNESS

SLEEP IS A REVERSIBLE STATE

WHERE CONSCIOUSNESS REMAINS

IN A SUBDUED STATE

BASED ON EEG AND EMG

SLEEP-WAKING WAS

OBJECTIVELY CLASSIFIED INTO

AWAKE AND SLEEP

ADDITIONAL PARAMETER,

CLASSICALLY AT LEAST EOG,

HELPED IDENTIFICATION OF

REM SLEEP (REMS)

(PGO AND HIPPOCAMPAL WAVES ALSO HAVE BEEN USED)

SLEEP-WAKING STAGES IN CAT

Thankachan & Mallick

Slow Wave Sleep 2

Slow Wave Sleep 1

Quiet Wakefulness

Active Wakefulness

EEG

EOG

EMG

Hipp

REM Sleep 100µV

25µV

50µV

50µV

4 Sec

SLEEP-WAKING STAGES IN RAT

Kaur & Mallick

HOW IS REM SLEEP (REMS)

REGULATED BY THE BRAIN? (Neural Regulation of REMS)

Depending on the firing rate of neurons during REMS, in

the brain there are

• REM-ON neurons (those increasing firing)

and

• REM-OFF neurons (those decreasing firing/silent)

REM-ON NEURON

Mallick et al., Sleep Res. Online, 1998

REM-OFF NEURON

Mallick et al., Sleep Res. Online, 1998

Based on recording of REM-ON and REM-OFF neuronal activities from isolated,

independent studies it was proposed that for REMS

i) activity of REM-ON neurons inhibit REM-OFF neurons;

ii) acetylcholine from REM-ON neurons inhibit the

Noradrenergic (NA-ergic) REM-OFF neurons

Hobson and McCarley, 1974; Sakai, 1980

QUESTIONS WE RAISED/ASKED

• Is cessation of NA-ergic REM-OFF

neuronal activities in locus coeruleus (LC) a

pre-requisite/pre-condition for REMS generation

or it is an associated phenomenon

• Activation of REM-OFF neurons in LC should

not allow REMS to happen

• Does acetylcholine inhibit the REM-OFF neurons

REM-OFF NEURON

HYPOTHESIS Singh & Mallick, Neurosci. Res., 1996

IF LC REM-OFF NEURONS

MUST STOP FIRING FOR

GENERATION OF REMS

THEIR ACTIVATION IN AN

ATTEMPT NOT TO ALLOW

THEM TO CEASE FIRING

WOULD CAUSE REMS LOSS

OR

AT LEAST WOULD

SIGNIFICANTLY

REDUCE REMS

Singh and Mallick, Neurosci. Res., 1996

Mild sustained stimulation of LC reduced REMS

Cessation of

activities of LC-

NA-ergic

REM-OFF

neurons is a pre-

requisite for the

generation of

REMS

Previously, activities of REM-ON and REM-OFF neurons

were recorded independently in separate animals,

in isolated experiments on different days.

For confirmation and to understand their temporal

correlation, we recorded in freely moving normally

behaving, surgically prepared chronic animals,

both REM-OFF and REM-ON neuronal activities

simultaneously along with electrophysiological

(EEG, EMG, EOG, PGO) waking-sleep-REMS patterns

SIMULTANEOUS RECORDING OF REM-OFF AND REM-ON NEURONS

Mallick et al., Sleep Res. Online, 1998

Temporal correlation between REM-ON and REM-OFF neuronal

firing

in vitro studies showed that

Acetylcholine depolarized LC neurons

i.e. not inhibition (Egan and North, 1985)

REM-OFF NEURONS MUST STOP FIRING FOR REMS GENERATION

BUT HOW ?

Hobson and McCarley, 1974; Sakai, 1980

Therefore, it was hypothesized In LC, excitatory cholinergic input from REM-ON neurons was translated into an inhibition

on REM-OFF neurons through GABA interneuron for REMS generation

Challenge was to simultaneously gather information on

Neuro-Micro-Anatomo-Pharmaco-Physiologico-Behavioral aspects

It was overcome by microinjection of agonist/antagonist of one or more types of

receptors in LC in various sequence/combination

Mallick et al., Neuroscience, 2001

REMS

REMS

Effect of local microinjection of cholinergic antagonist (scopoloamine)

and agonist (carbachol) bilaterally into the LC on REMS

Mallick et al., Neuroscience, 2001

REMS duration per episode was not affected, however,

frequency of REMS generation was increased

REMS

REMS

Effect of local microinjection of GABA-ergic antagonist (picrotoxin) and GABA

bilaterally into the LC on REMS

Mallick et al., Neuroscience, 2001

REMS duration per episode was significantly affected, however,

frequency of REMS generation remained unaffected

REMS

REMS

Effect of local microinjection of cholinergic and GABA-ergic antagonist/agonist in various

combinations/sequences into the LC on REMS

Mallick et al., Neuroscience, 2001 REMS could not be sustained

REMS duration per episode was reduced in (A); it was increased in (B), while in

(C) REMS did not continue

Mallick et al., Neuroscience, 2001

Other inputs

Kaur et al., Synapse, 2001

Prepositus

hypoglossus

(PrH)

Comparison of the effect PrH Stimulation and microinjection of

GABA and Picrotoxin in LC on REM Sleep

Mallick et al., Neuroscience, 2001 ; and Kaur et al., Synapse, 2001

PHYSIOLOGICAL VALIDITY?

HYPOTHESIS

IF THE PROPOSED NEURAL CONNECTIONS

ARE EXPERIMENTALLY DISTURBED SO

THAT THE NA-ergic LC-REM-OFF NEURONS

REMAIN ACTIVE,

REMS SHOULD BE SIGNIFICANTLY

REDUCED

AND SIMULTANEOUSLY

REMS LOSS ASSOCIATED SYMPTOMS

SHOULD BE EXPRESSED/OBSERVED DUE TO

ELEVATED LEVELS OF NA

EVEN IN NORMAL ANIMALS (Contd…)

Mallick et al., Neuroscience, 2001

Neurotransmitter Release

PHYSIOLOGICAL VALIDITY?

HYPOTHESIS

We had already shown that REMSD increased Na-K ATPase activity and it

was due to elevated level of noradrenalin (NA) in the brain

(Gulyani & Mallick, Neuroscience, 1995; Mallick et al., J. Neurochem., 2000).

Therefore, we proposed that

i) GABA-antagonist, picrotoxin, into LC should not allow REM-OFF

neurons to cease activity resulting in increased Na-K ATPase activity;

ii) Modulation of Na-K ATPase activity in LC should alter REM-OFF

neuronal activity and REMS

Picrotoxin (every 6h) bilaterally into the LC for 48h

reduced REMS (A) and increased Na-K ATPase activity (B) significantly

Kaur et al., Behav Brain Res. 2003

Per

cen

t ti

me

(mea

n

± S

.E.M

.)

0

5

10

15

20

25

30

35

40

*

AW REMS DS SWS QA

Baseline Picrotoxin

A.

Kaur et al., Behav Brain Res. 2003 Picrotoxin Control

0

5

10

15

20 ** B.

Gulyani and Mallick, J. Sleep. Res., 1993

We had confirmed that the REMS loss associated increase in Na-K ATPase activity is

actually mediated by elevated level of NA (Gulyani and Mallick, 1995; Mallick et al., J. Neurochem, 2000)

Comparison of Na-K ATPase activity in rat brain REMSD A. B. Picrotoxin every 6h into LC

Kaur et al., Behav Brain Res. 2003

Picrotoxin Control 0

5

10

15

20 **

Effect of anti-ouabain antibody into LC on sleep-waking-REMS

Jaiswal et al., J. Sleep Res., 2009

ACKNOWLEDGEMENT

I thank all my co-workers for their

contributions in the studies presented here

Funding from the following Indian agencies is acknowledged :

BIOSCIENCE AWARD, CSIR, DBT, DST, ICMR,

J C BOSE FELLOWSHIP, JNU, UGC

Sleep disorders and therapy Related Journals

• Alzheimer's

Disease &

Parkinsonism

• Brain Disorders &

Therapy

Annual Summit on Sleep Disorders and Medicine August

10-12, 2015 San Francisco, USA

2nd International Conference on Alzheimer's Disease and

Dementia September 23-25, 2014 Valencia, Spain

Sleep disorders and therapy

Related Conferences

OMICS Group Open Access Membership

OMICS publishing Group Open Access Membership

enables academic and research institutions, funders and

corporations to actively encourage open access in

scholarly communication and the dissemination of

research published by their authors.

For more details and benefits, click on the link below:

http://omicsonline.org/membership.php